ENST00000693560.1:c.-411G>A

Variant names:

• chr10-87863539-G-A
• rs587781959
• ENST00000693560.1:c.-411G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.-930G>A (NC_000010.10:g.89623296G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PM2: Absent in large sequenced populations LINK:https://erepo.genome.network/evrepo/ui/classification/CA000640/MONDO:0017623/003

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN ENST00000693560.1 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:4 B:1
• Conservation: PhyloP100: 2.31
• Publications: 0 publications found

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

KLLN Gene-Disease associations (from GenCC):

• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 4

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

MLDHR (HGNC:55481):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.-931G>A		upstream_gene_variant		ENST00000371953.8	NP_000305.3
KLLN	NM_001126049.2	c.-1052C>T		upstream_gene_variant		ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.-931G>A		upstream_gene_variant		1	NM_000314.8	ENSP00000361021.3
KLLN	ENST00000445946.5	c.-1052C>T		upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2
MLDHR	ENST00000692337.1	c.-20G>A		upstream_gene_variant				ENSP00000509326.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 233488 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 118760

African (AFR) AF: 0.00 AC: 0 AN: 6574

American (AMR) AF: 0.00 AC: 0 AN: 6906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8590

East Asian (EAS) AF: 0.00 AC: 0 AN: 22170

South Asian (SAS) AF: 0.00 AC: 0 AN: 2578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 149440

Other (OTH) AF: 0.00 AC: 0 AN: 15350

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 20, 2020

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.-930G>A (NC_000010.10:g.89623296G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2: Absent in large sequenced populations

not provided Uncertain:1

May 05, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with Cowden syndrome and thyroid cancer (PMID: 12844284 (2003)), and in an individual with thyroid cancer who did not meet clinical criteria for Cowden syndrome (PMID: 21417916 (2011)). Based on the available information, we are unable to determine the clinical significance of this variant.

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 09, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-930G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 930 bases upstream from the first translated codon. This alteration was detected in a patient that was reported to have Cowden syndrome (CS), but clinical details were not provided and the alteration was predicted to alter a putative Sp1 transcription factor-binding site (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This variant was predicted to alter PTEN RNA structure by in silico analysis (Sabarinathan R et al. Hum. Mutat. 2013 Apr;34:546-56). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence for this variant is limited at this time, the clinical significance of this alteration remains unclear.

Glioma susceptibility 2 Uncertain:1

Feb 18, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTEN-related disorder Benign:1

Sep 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		2.3
PromoterAI		-0.22	Neutral
Mutation Taster		=107/193	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587781959; hg19: chr10-89623296;